Neural transplantation of fetal ventral mesencephalic (VM) tissue has been studied for the past two decades as a potential surgical strategy for the treatment of Parkinson's disease (PD). Clinical trials in Parkinsonian patients have been conducted in several centres worldwide with more than 200 patients receiving fetal transplants into the striatum (Mehta et al., Can. J. Neurol. Sci., 24, pp. 292–301, 1997; Olanow et al., TINS, 19, pp. 102–109, 1996; Rehncrona et al., Adv. Tech. Stand. Neurosurg., 23, pp. 3–46, 1997; Tabbal et. al. Curr. Opin. Neurol., 11, pp. 341–349, 1998). Survival of the grafts has been documented with positron emission tomography (PET) scanning (Freeman et al., Ann. Neurol., 38, pp. 379–388, 1995; Remy et al., Ann. Neurol., 38, pp. 580–588, 1995; Wenning et al., Ann. Neurol., 42, pp. 95–107, 1997) and postmortem studies (Kordower, et al., N. Engl. J. Med., 332, pp. 1118–1124, 1995). Although the results of these trials have been promising, (Hauser et al., Arch. Neurol., 56, pp. 179–187, 1999; Wenning et al., Ann. Neurol., 42, pp. 95–107, 1997) clinical efficacy has not reached the stage for neural transplantation to become a routine therapeutic procedure for PD. Implantation trauma, which decreases graft survival, and inadequate reinnervation of the host striatum due to suboptimal distribution of graft deposits are considered detrimental factors in achieving optimal clinical efficacy. Decreased implantation trauma and a more complete reinnervation of the dopamine-depleted striatum have been achieved in animal models of PD by decreasing the size of the implantation cannula and increasing the number of deposits of fetal dopaminergic cells (Nikkhah et al., J. Neurosci., 15(5), pp. 3548–3561, 1995; Nikkhah et al., Neurology, 63, pp. 57–72, 1994). These modifications to the implantation technique have produced improvements in host reinnervation and functional recovery in the rodent model of PD (Nikkhah et al., J. Neurosci., 15(5), pp. 3548–3561, 1995; Nikkhah et al., Neurology, 63, pp. 57–72, 1994).
The use of neural transplantation to treat neurological conditions such as PD has the potential to be an important therapeutic strategy in the near future. There is strong evidence of long-term survival of transplanted dopaminergic neurons (Kordower et al., N. Engl. J. Med., 332, pp. 1118–1124, 1995) and clinical results are promising (Hauser et al., Arch. Neurol., 56, pp. 179–187, 1999; Wenning et al, Ann. Neurol., 42, pp. 95–107, 1997). Transplantation in patients with Huntington's disease has also been reported (Kopyov et al., Cell Transplantation for Neurological Disorders, Humana Press, pp. 95–134, 1998) and porcine xenografts are being studied in clinical trials (Deacon et al., Nature Medicine, 3, pp. 350–353, 1997; Isacson et al., al., Nature Medicine, 3, pp. 474–475, 1997). A great deal of experimental work in animals is being conducted for novel cell types as an alternative source to human fetal tissue for neural transplantation. This research may expand the use of reconstructive-strategies in the future (Borlongan et al., Exp. Neurol., 149, pp. 310–321, 1998; Fitoussi et al., Neuroscience, 85, pp. 405–413, 1998; Svendsen et al., Exp. Neurol., 137, pp. 376–388, 1996).
In view of the above comments, neural transplantation holds great promise as a method of achieving a more complete reinnervation of neural tissue and therefore, functional recovery, providing (1) the number of cell deposits to a target site in a subject can be maximized, (2) the distribution of graft deposits can be optimized, and (3) implantation trauma caused by multiple insertions of a transplantation device can be avoided.
Presently, a neural transplantation device and method used for administering neural cells and/or tissue is described by Cunningham in U.S. Pat. No. 5,792,110 wherein the device essentially comprises a guide cannula for penetrating a selected transplant site in a subject to a predetermined depth, and a delivery cannula with a single opening for delivering neural cells and/or tissue to the subject. The guide and delivery cannulas both have an interior lumen and openings at their proximal and distal ends. The delivery cannula, however, has an outer diameter and particular shape that enables it to fit and move within the interior lumen of the guide cannula. Furthermore, the delivery cannula is capable of protruding through the distal end of the guide cannula by way of a flexible distal end portion which enables it to be deflected at a suitable angle from the guide cannula. The method of delivering cell deposits essentially involves advancing the guide cannula into the brain to the transplant site wherein the delivery cannula, which carries the cells, is advanced within the lumen of the guide cannula, and beyond the distal opening of the guide cannula. Cells are deposited along a first extension pathway by advancing the delivery cannula to a distal targeted site and performing a series of injections alternated with incremental retraction of the delivery cannula at predetermined sites along the path. The three dimensional array is essentially achieved by executing several penetrations of the delivery cannula at other distal transplant sites to achieve a similar arrangement of cell deposits along different extension paths located an equidistance from one another.
The delivery device and method described by Cunningham possesses a number of certain disadvantages. In particular, because the outside diameter of the guide cannula is relatively large, e.g. 1.07 mm, the insertion of the guide cannula into the brain during standard neural transplant procedures has the potential to cause localized trauma to the tissue and ultimately result in cell death and poor graft integration. Other disadvantages associated with a transplant cannula having a large diameter is a lower precision in graft placement and a lower reliablity in delivery of very small volumes to a selected site in a subject. In addition, the design of this particular transplantation device only allows multiple grafts to be delivered along a single path with each insertion of the delivery cannula. Supplementary grafts at sites which are not along this path, require the delivery cannula to be removed and reinserted along a new path. Although it is desirable to deliver multiple grafts along different paths in a three dimensional configuration, reinsertion of the cannula increases the risk of trauma to the brain of the transplant recipient with each new penetration thereby contributing to low and variable graft survival and functional recovery. Furthermore, because the delivery cannula is deflected at an angle from the guide cannula and causes the delivery cannula to enter the brain tissue in an oblique fashion, this is also potentially harmful to the brain. Another disadvantage of the Cunningham transplantation device is that the shape of the opening at the extreme distal end of the delivery cannula is not blunt and is potentially harmful to the brain. Moreover, the opening of the tip of the delivery cannula has the potential to become obstructed in the course of performing multiple insertions of the delivery cannula, thereby eventually preventing ejection of a cell and/or tissue suspension.
Accordingly, there is a need for a neural transplantation device and method which can precisely deliver a predetermined volume amount of cells and/or tissue to a selected transplant site in a three dimensional configuration without having to perform multiple insertions of the device. Furthermore, such a device and method should minimize tissue damage and provide for increased survival of the cells and functional integration of the graft in the subject.
According to the present invention, there is provided a neural transplantation system, comprising a microinjector, transplantation cannula and bullet guide in combination with a syringe mounted to a stereotactic frame, which affords a simple, reliable and safe system for improved delivery and maximization of the number of cell graft deposits to the host brain with minimal trauma using a unique spiral technique.